Bioenergetic and proteomic profiling to screen small molecule inhibitors that target cancer metabolisms.
Animals
Drug Discovery
/ methods
Drug Evaluation, Preclinical
/ methods
Electron Transport Chain Complex Proteins
/ drug effects
HeLa Cells
Humans
Macrocyclic Compounds
/ pharmacology
Mitochondria
/ drug effects
Neoplasms
/ drug therapy
Phenotype
Photoaffinity Labels
Proteomics
/ methods
Small Molecule Libraries
Two-Dimensional Difference Gel Electrophoresis
/ methods
Cancer metabolism
NPL40330
Phenotypic screening
Proteomic profilin
Respiration inhibition
Unantimycin A
Journal
Biochimica et biophysica acta. Proteins and proteomics
ISSN: 1878-1454
Titre abrégé: Biochim Biophys Acta Proteins Proteom
Pays: Netherlands
ID NLM: 101731734
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
28
02
2018
revised:
30
05
2018
accepted:
01
06
2018
pubmed:
9
6
2018
medline:
11
9
2019
entrez:
9
6
2018
Statut:
ppublish
Résumé
Cancer cells can reprogram their metabolic machinery to survive. This altered metabolism, which is distinct from the metabolism of normal cells, is thought to be a possible target for the development of new cancer therapies. In this study, we constructed a screening system that focuses on bioenergetic profiles (specifically oxygen consumption rate and extracellular acidification rate) and characteristic proteomic changes. Thus, small molecules that target cancer-specific metabolism were investigated. We screened the chemical library of RIKEN Natural Products Depository (NPDepo) and found that unantimycin A, which was recently isolated from the fraction library of microbial metabolites, and NPL40330, which is derived from a chemical library, inhibit mitochondrial respiration. Furthermore, we developed an in vitro reconstitution assay method for mitochondrial electron transport chain using semi-intact cells with specific substrates for each complex of the mitochondrial electron transport chain. Our findings revealed that NPL40330 and unantimycin A target mitochondrial complexes I and III, respectively.
Identifiants
pubmed: 29883687
pii: S1570-9639(18)30092-X
doi: 10.1016/j.bbapap.2018.06.001
pii:
doi:
Substances chimiques
Electron Transport Chain Complex Proteins
0
Macrocyclic Compounds
0
Photoaffinity Labels
0
Small Molecule Libraries
0
unantimycin A
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
28-37Informations de copyright
Copyright © 2018 Elsevier B.V. All rights reserved.